The efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumours has been disappointing to date. However, new data from a phase I trial in patients with recurrent high-grade gliomas (rHGGs) demonstrate the therapeutic potential of post-surgical intracranial delivery of CAR T cells targeting IL-13 receptor α2 (IL-13Rα2), a cancer-testis antigen that is often ectopically expressed in these hard-to-treat cancers.

The CAR T cells evaluated in this trial were designed to selectively target IL-13Rα2 over IL-13Rα1, a low-affinity isoform more ubiquitously expressed in non-malignant tissues, by using E12Y-mutated IL-13 ligand as the targeting moiety. CAR T cell manufacturing was successful for 89 of 92 patients with IL-13Rα2-expressing rHGGs who underwent apheresis, although rapid disease progression precluded surgery and/or CAR T cell infusion in 24. The remaining 65 patients were allocated to five treatment arms testing intratumoural CAR T cell delivery following either biopsy (arm 1; n = 2) or surgery (arm 2; n = 18), intraventricular delivery following surgery (arm 3; n = 11), or both routes (arms 4 and 5; n = 12 and 22, respectively); arm 5 also involved an optimized manufacturing process that enriches for naive, stem-cell memory and central memory T cells, as opposed to only the latter subset in arms 1–4.

迄今为止，嵌合抗原受体（CAR）T细胞治疗实体瘤的疗效令人失望。然而，来自复发性高级别胶质瘤 (rHGG) 患者的 I 期试验的新数据证明了手术后颅内递送靶向 IL-13 受体 α2 (IL-13Rα2)（一种癌症睾丸）的 CAR T 细胞的治疗潜力。抗原通常在这些难以治疗的癌症中异位表达。

本试验中评估的 CAR T 细胞旨在通过使用 E12Y 突变的 IL-13 配体作为靶向部分，选择性地靶向 IL-13Rα2 而不是 IL-13Rα1（一种在非恶性组织中更普遍表达的低亲和力亚型）。 92 名接受单采术的表达 IL-13Rα2 rHGG 的患者中，有 89 名患者的 CAR T 细胞制造成功，但其中 24 名患者因疾病快速进展而无法进行手术和/或 CAR T 细胞输注。其余 65 名患者被分配到五个治疗组，测试肿瘤内注射活检（第 1 组；n =  2）或手术（第 2 组；n =  18）后进行 CAR T 细胞递送，手术后心室内递送（第 3 组；n  = 11），或两种途径（第 4 组和第 5 组；n  =分别为 12 和 22）；第 5 臂还涉及优化的制造工艺，丰富了初始干细胞记忆和中央记忆 T 细胞，而不是第 1-4 臂中的后一个子集。